Many mRNAs that are located in dendrites encode for proteins that are critically important for particular forms of synaptic plasticity. Indeed, local protein synthesis in dendrites is required for many alterations in synaptic efficacy. Little is known, however, about the mechanism of translation in dendrites and how translation may be regulated by synaptic events. Most eukaryotic mRNAs are thought to initiate translation by a cap-binding/scanning mechanism. Some mRNAs can also initiate translation in a cap-independent manner from internal ribosomal entry sites (IRESes). The working hypothesis is that the 5' leader sequences of dendritically localized mRNAs contain IRESes. The presence of IRESes in mRNAs could increase the efficiency of translation at a cellular site where many of the components of the translational machinery may be limiting. Furthermore, the mechanisms that regulate cap and IRES dependent translation may be unique allowing for differential regulation of translation in response to synaptic stimuli and environmental conditions. The proposed studies will utilize cell lines and primary neurons to 1) examine whether the 5' leaders of dendritically localized mRNAs exhibit IRES activity and determine the cis-elements within the 5' leaders that promote internal initiation, 2) determine the contribution of the cap and IRES to translation in dendrites, and 3) determine whether neural activity or environmental conditions such as hypoxia, differentially affect cap and IRES dependent translation. These studies will provide novel insights into the mechanisms of translation in neurons and provide a better understanding of how synaptic events and stress can lead to alterations in synaptic plasticity, and consequently, to learning and memory.